Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

Sewa Rijal, Shaun Fleming, Nik Cummings, Natalie Rynkiewicz, Lisa Michelle Ooms, Nhu-Y N Nguyen, Tse-Chieh Teh, Sharon Avery, Julie McManus, Anthony Troy Papenfuss, Catriona Ann McLean, Mark Andrew Guthridge, Christina Anne Mitchell, Andrew Wei

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

Abstract

Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.
Original languageEnglish
Pages (from-to)2815-2824
Number of pages10
JournalBlood
Volume125
Issue number18
DOIs
Publication statusPublished - 30 Apr 2015

Cite this

Rijal, S., Fleming, S., Cummings, N., Rynkiewicz, N., Ooms, L. M., Nguyen, N-Y. N., Teh, T-C., Avery, S., McManus, J., Papenfuss, A. T., McLean, C. A., Guthridge, M. A., Mitchell, C. A., & Wei, A. (2015). Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML. Blood, 125(18), 2815-2824. https://doi.org/10.1182/blood-2014-09-603555